PROJECT SUMMARY: Approximately 31 million Americans suffer from Chronic Kidney Disease, which is characterized by a progressive decline in kidney function. One of the major contributing factors to Chronic Kidney Disease is high blood pressure or hypertension. Despite several classes of anti-hypertensive drugs, blood pressure remains uncontrolled in more than half of patients. This underscores the need for new drug targets. A feature of uncontrolled blood pressure is dysregulated renal sodium handling. Sodium handling by the kidney is the cornerstone of whole body salt and water balance, and subsequent blood pressure homeostasis. Intracellular mechanisms that regulate renal sodium transporter expression and/or activity offer a new direction for the next generation of blood pressure therapies. By integrating cellular and molecular biology with animal models, our long-term research objective is to identify and exploit signaling pathways that regulate renal sodium transporters and subsequently sodium handling and blood pressure. Calcineurin (CnA) is a new player in the regulation of renal sodium handling and has been identified to be involved in hypertension. Furthermore, clinical and experimental data support a role for CnA in regulation of renal sodium transporters and blood pressure. Consistent with the literature, preliminary studies show that CnA inhibition with tacrolimus (general inhibitor) stimulates the upregulation of the renal sodium chloride cotransporter (NCC). However, understanding of the underlying mechanisms of NCC regulation, renal sodium handling and blood pressure control are limited by a gap in knowledge regarding the specific role of each renal CnA isoform (CnA? and CnA?). This R21 grant will delineate the contribution of each CnA isoform to blood pressure regulation. To this end, we take advantage of innovative transgenic mouse models and cell lines. The outcomes of this R21 grant will enhance our knowledge of the specific mechanisms by which CnA isoforms regulate blood pressure as well as inform the development of anti-hypertensive and immunosuppressive therapies.